Category Archives: Clinical Trials

Kidney cancer patients are stunned by their diagnosis, anxious to make a treatment decision, and simply not know what to expect. If you are struggling with the issue of surgery to remove the tumor/kidney or to start with a med, you need to read this. Deb Maskens, Kidney Cancer Patient and Patient Advocate, our guest writer isa valued member of our disease community and currently serves on the Renal Task Force for the National Cancer Institute. A series of links below will also be helpful. (My extra comments will be in italics, like this. )Welcome aboard, Deb!

As a community of kidney cancer patients, we hear from newly diagnosed patients looking for treatment options. This is written for those patients, and for patient advocates who help patients navigate through their treatment decisions.

The challenge: this clinical trial is available at many locations across the U.S. and Canada, but patients must ask about it BEFORE they have a nephrectomy. Their own doctors may be unaware of the trial and how to work with the trial centres. In many places, patients get booked for surgery prior to learning about this option. That would be too late for a trial like this–it gives a drug therapy before the surgery for a brief period. (In one of the t wo arms, there is medication before the surgery.)

Why Might Patients Consider this Trial?

For years, the standard of care for early stage kidney cancer has been to remove the tumour surgically, sometimes with the entire kidney–either a partial or full nephrectomy. That was the end of treatment and the beginning of surveillance to watch for any signs of recurrence. (And early stage tumors can be quite large–up to 7cm or about 2 3/4″.)

Now we hope to prevent a recurrence of disease. Since advanced or metastatic kidney cancer is still incurable for the vast majority of patients, this is a worthy goal. With preventive or ‘adjuvant’ treatments, maybe we can stop the disease before it gets to the lungs, liver, bones — to those places where it begins to threaten our lives. Other cancers use this approach and offer patients a real chance to avoid recurrence.

Adjuvant – and Perhaps One Step Better to Neo-Adjuvant

We’ve seen trials for “Adjuvant” (or preventative) therapy which hope to prevent recurrence (treatments given immediately after nephrectomy). But one trial goes one step better – it’s for “Neo-Adjuvant” (before nephrectomy) as well as Adjuvant (after).

Patients may want to rush to surgery to “get it out”. In reality, those tumours have generally been growing slowly, undetected for many years. Kidney cancer surgery is rarely an emergency. There is usually time for a second opinion and to check out any newer approaches.

Here’s the thought: given that the tumour cells have gone undetected and tolerated by the immune system for so long, can put those millions of cells to work and make them “show their calling cards” to our immune system before we take them out?

Combining Neo-Adjuvant and Adjuvant Treatment – PROSPER-RCC

The Phase 3 clinical trial called PROSPER-RCC (NCT03055013) is for patients whose tumors are 7cm (2 ¾”) and larger in size, but not spread beyond the kidney area. These patients are at greater risk of spread of the cancer than those with Stage I or with smaller tumors.

Based on earlier studies, nivolumab (Optivo) is now approved for advanced kidney cancer. This is a trial to test whether there is a benefit when nivolumab is given immediately before and after a nephrectomy when tumor cells might have spread outside the kidney but are too small (microscopic) to see on scans. (Typically a patient without spread of disease would not be treated, but monitored.)

The Rationale for PROSPER-RCC: Why It Might Be Helpful

Here’s what I’ve learned:

Checkpoint inhibitor treatments with PD-1 blocking drugs like nivolumab seem to work best when the immune system may be being turned off by this cellular growth pathway. Cancer is deceptively clever and some tumours can express a protein, PD-L1. This protein can turn off our immune cell responses that recognize and fight the cancer. There was a hint of this with some positive data that indicates that these drugs work best in patients whose tumors were “PD-L1 positive”. (PD means Programmed Death and PD-L Programmed Death Ligand or connector. Death to the cells, and the signalling loop that hinders the immune response.)

In theory, when the kidney tumour is in place, there are millions of cancer cells. All of those tumour cells send off multiple negative signals to the immune system to stop it from working. However, if a checkpoint inhibitor was used and stopped those blocking signals, the immune system would have a big wake-up call – e.g., lots of targets with which to build an army of T cells. In theory, these newly educated T cells would later turn into memory cells. (If the body can maintain these memory cells, they would continue to fight any return of disease.)This is much like what happens when we are exposed to certain bacteria or viruses. Once we get exposed to the bug, we don’t usually get it again. Our immune cells have learned (“immunity”) how to kill it more quickly the next time before it turns into a full blown cold. Similarly, if these anti-RCC immune cells ever see one of these tumor cells anywhere in our bodies again, they would know to attack and kill them even if there is no drug in the patient and has not been for some time.

Surgery is still the main treatment to control early stage kidney cancer. But it will also remove the majority of targets (PD-L1) that the checkpoint drug uses to rev up the immune system. Giving the checkpoint inhibitor before surgery may maximize/optimize the drug’s ability to wake up the immune system and build that T cell army.

So the surgery is important. But let’s assume a few cells might be still circulating and have gone undetected for some time. They could still show up later on a scan as an enlarged lymph node or spot somewhere. A boost of the same checkpoint inhibitor right after the surgery could then be used to remind the immune system to continue to look for those cells and kill/eliminate them when they are small. In theory, the immune system will remember what the past “trouble” was: “Hey, haven’t I seen you before?”

From what I understand, this theory worked well in mice. The checkpoint inhibitors worked better if the primary tumour was there to help provide “a target” to activate the immune system first before the tumor was removed. While we’re not mice, this makes sense, no?

Trial Design: What Really Happens to the Patient in the Trial

PROSPER-RCC will place patients randomly into two groups:

Group One gets two infusions of nivolumab before surgery (at about 28 days and 14 days before surgery). Following that nephrectomy, the patient will receive more infusions of nivolumab. This is for 9 months post-surgery altogether, with 12 more doses.

Group Two gets the usual standard of care: upfront nephrectomy, partial or radical nephrectomy, and will be followed by close observation at an expert centre.

Two arms/groups: BLUE arm with surgery and monitoring by the trial team, the standard of care; the RED arm with medication before to surgery, followed by more after the surgery.

It is important to note that no patient on this trial receives any intravenous placebo/inactive treatment. Every patient is treated. Each patient will have either the experimental treatment or the standard of care. All are under close observation at the trial centre. This trial has been designed and discussed with patient advocates and is supported by the NCI.

or call the office of the Principal Investigator, Dr. Lauren Harshman, at: 617-632-2429

Deb’s Disclaimer:

As a patient and advocate for kidney cancer patients, I have been delving into the world of clinical trials and trying to understand as much as I can. I’m not a scientist, but I am a patient with this disease, so I bring that lens, along with some abilities to translate science into understandable terms. As a volunteer, I have no financial interest in this trial or any specific medications. @DebMaskensKCC; dmaskens@rogers.com

With the headline, “Nivolumab Shows a Substantial Objective Response Rate in Refractory Non-Clear-Cell Renal Cell Carcinoma”, the article should be welcome to all of those in the in the non clear cell RCC world. Clear cell is the most common, the garden variety of renal cell carcinoma. This is welcome news, as the non clear cell patients get very little attention from the research world. Though the patient with nccRCC might interpret this as, “Good news! Now that they know what to do for me!” , it is just not the case. Rarely is the news all that good or all that simple.

Let’s back up here and lay the groundwork. Clear cellRCC, or ccRCC is the most common of about 10 RCCs. They all land in the kidney, but can vary widely. ccRCC may be about 65% to 85% of the cases of kidney cancer, with the rarer non-ccRCCs making up the rest. Maybe 15-35% of the RCCs are considered rare, with the most common Papillary Type I, Papillary Type II, chromophobe, clear cell papillary, collecting duct/Bellini’s, medullary, translocational (not to be confused with transitional, etc, etc.) and to make it still more confusing, unclassified RCC. But when the most common is described as either 65% of the whole or 85% percent, you have to question if there is clarity in that category!

Clinical trials for RCC have usually only included patients who had clear cell. The reasons are simple; it is the biggest group, the patients can be more readily found, and that is the largest group in need of the medications. But the patients with nccRCC are really also terribly underserved. Back in the day, none of us had many options beyond surgery, so little distinction was made. The prognosis was grim all around, once the cancer had spread.

But the new world of precision medicine, in its name alone, reminds us that the meds need to be developed more precisely, that they be given to the right patients at the right time. The general crap shoot or “wild-ass guessing”, as a friend says, still remains. The latest (not necessarily greatest) group of meds are the newish immune therapies. You have seen their ads, no doubt.

One of those is Opdivo or nivolumab, its research name. It tries to unblock some of the inhibiting mechanisms that prevent the immune system from doing its job, but it has been tested in trials only with clear cell patients. BUT, that does not mean that only clear cell patients are being prescribed the meds–this, thanks to the slightly wild west of the US medical system, that can truly go beyond the FDA approved medication guidelines.

This study, which will be formally presented at ASCO in June, 2017 was announced with the headline above, “Nivolumab Shows a Substantial Objective Response Rate in Refractory Non-Clear-Cell Renal Cell Carcinoma”. The researchers are NOT in charge of the headlines, so we must dig deeper and see what this study really means to the patients with nccRCC

I tried to sort out what it means–or does not mean. My quick review is that it does not give a great deal of clarity to the majority of those nccRCC patients. A more complete report may improve upon this. Based on this link, I offer the following:

http://www.practiceupdate.com/news/16132/67/10?elsca1=

“I am always concerned that these new study reports are characterized carefully. They are always more complex and incomplete than I would like. A patient in a forum says this tells of ‘good’ responses, and especially so for the non clear cell group, but s does ‘good’ really mean generally a benefit to those rarer nccRCCs? Until a fuller report emerges, I can only note the following:

There were 23 patients, from three centers, with a median age of 59. Surprisingly 30% were African -American. This may tell us that there are more African-Americans with the rarer non-clear cell RCCs, or could reflect the local population of the three centers. Only 23 patients and with a mix of diseases will never meet the statistically critical requirements to reach the level of excellent evidence–but it may be all we have at this point.

All 23 had non-clear cell, but nearly half had ‘unclassified’ RCC, quite a high rate. Usually that is considered to represent between 1 to 4% of renal tumors. Most of the rest were papillary, but they generally make up the largest percentage of nccRCCs. No distinction is made here between Papillary Type I or Type II, which are really quite different diseases. Papillary Type I and II are the most common of the uncommon, non clear cell RCCs, and are readily distinguished from each other. This would be valuable info, and wonder if this was noted in the fuller report.

Only 3 of 4 patients had nephrectomies before the trial treatment. Were 1 of 4 patients too sick to be given the standard of care of surgery or were their doctors unaware of that? How does this affect the study, and were the no nephrectomy patients from one center or with one subtype? We do not know the reason for this high rate of no surgery, and at a time in which it is clear that the removal of the tumor is a great benefit to the patient, metastatic or not.

Two-thirds had metastatic disease at the time of diagnosis. Of the total 23, 74% had a prior treatment, mostly Sutent or Votrient. Of these patients with prior treatments, 26% had TWO such treatments. Thus these patients had already received treatments that were not directly approved for their subtypes. This is not too rare in the US, where we have greater leeway from our prescribing doctor than do patients elsewhere. But how does this fit in with the relatively low rate of nephrectomies?

This report does not say how quickly they were treated, i.e., how long from initial diagnosis until treatment with Nivolumab?A patient with Papillary Type II found to have no metastatic disease at the time of diagnosis, but who received a nephrectomy, was monitored for a year or so, then went on one or more systemic therapy is quite different from the patient with an unclassified RCC, metastatic at the time of diagnosis, not given a nephrectomy, though treated quickly with Nivolumab. What can be learned when there are such wide variations in just 23 patients that would be helpful to the Papillary Type 1 patient?

The follow up period was a median of 6.5 months, which seems very short, especially when the median Progression Free Survival of the responders was 4.2 months. The median OS is not given. That certainly may reflect an ongoing study situation, or a failure to provide a longer period of follow up.

As to objective response, 6 of the 21 evaluable patients (29%) had a Partial Response, which would likely be a 30% reduction in metastases. Another 4(19%) had Stable Disease. Two of the 23 patients died, but not from the treatment. (Assume that had to be due to the disease, but certainly indicates that for nearly 10% of the patients, this was not at all effective.)

When the final analysis was done, nine patients were still receiving Nivo. Newly recruited patients might still be in treatment at that time, but those recruited earlier may have gone out of the trial at the same time. It is important to not that Nivolumab treatments were stopped in three patients due to intolerance, and six more had postponed treatment, i.e., 9 of the 23.

Certainly we need to find meds which create responses for nccRCC patients. However, I am concerned we draw any certain conclusions from this study. Indeed, it is “good” to know that the treatment was tolerable for the majority of the participants, but not so good to read that 6 of the 21 patients had to postpone treatment, and three were removed from treatment due to intolerable/toxic side effects. We also do not know which subtypes seem to have shown responses, which would have been qutie easy to report. Did the group with Papillary Type II do generally better that the majority “unclassified” group? No answer from this stury report. And in the back of my head, I keep wondering why in the world there were so many unclassified patients in this small study? Was there a standard pathology review, or could these patients been misdiagnosed by one pathologist. Typically there is a single pathologist which can standardize the reporting. Were all these patients properly diagnosed?

Just wishing there were greater clarity and hoping to get a fuller report, post ASCO.

Without a doubt, the ‘good’ that comes from this sort of report begins with the recognition that the nccRCC group is underserved by the research community> They probably have the poorest outcomes, rarely have a clear diagnosis, and must wait for the ever popular “further research is warranted.” But all must be aware that these very small observational studies must be reviewed very carefully for what they show or do not show. Again, one to watch at ASCO, but not enough to make a major change in treatment for any one with a non clear cell RCC.

PS. Does your doctor know that there are at least four subtypes of clear cell–the big ‘common’ group–which have clearly different survival patterns? Thought so.

Another new drug for those of us with ‘unresectable and advanced” kidney cancer! YEA or is is just, yea? What does this mean to the patient in this situation as he struggles to get the best treatment possible?

The approval is for Levatinib in combination with Everolimus (Afinitor) for advanced kidney cancer or unresectable (surgery not possible) kidney cancer in patients who have had previous TKI treatment–Sutent, for example. This was based on a Phase II trial, so a bit unusual in that regard. Generally the FDA waits until there is a larger Phase III trial, so this reflects the need for better second-line treatments.

It is always great to have another tool against kidney cancer, and on top of the recent approval of Nivolumab (Opdivo) and Cabozantinib (Cometryx), but do note that all three are for second line use, after the first line meds have failed. Current first line drugs include high dose interleukin, Sutent and others.

All the patients in this trial had previously used and quit responding to the first line TKIs, and are compared in three arms

Arm 1) Lenvatinib alone–52 patients—didn’t make the grade

Arm 2) Everolimus alone–51 patients—standard of care for second line

Arm 3) Lenvatinib & Everolimus in combo–51 patients–the new approval.

Not a very big trial, so harder to make broad judgements!

Everolimus is already approved for second line use, and Lenvatinib alone was NOT approved except in combination with Everolimus. With that, just ignore Arm 1. The big news is that the combo improved median Progression Free Survival (PFS) in the combo to 14.6 months vs 5.5 months with Everolimus. The median gives us the POINT in time at which half got “progressed” on their disease, ie, the damn stuff grew, while the other half had not yet had progression. Not an average, so half of the combo patients had PFS by 14.6 months, and the other combo half did not have PFS until after that time.

The median Overall Response Rate (ORR) was not very high–but quite typical–and important to understand. The combo patients had a 37% ORR, so about 1 in 3 had a measurable response. That compared to just 6% with everolimus. The most important measure to patients is median Overall Survival. This is usually measured when one-half of a patient group has died, so there are always patients who live beyond that median point. The combo OS was 25.5months vs the Evero alone OS of 15.4 months. There was no mention I could find whether there were patients alive at this point, but assume there were. Love to know if there are very long term survivors in the combo group, and what makes them more likely to have that response!

In the combo, 29% of the patients discontinued treatment due to side effects and with Everolimus alone, 12% discontinued. However, both groups had large number of reduced dosages and/or dose interruptions, 89% in the combo group, and 54% in the evero group. Read: some tough side effects.

The most serious side effect in my opinion was that renal failure occurred in 11% of patients in the combo, 5 of the 51 patients. Grouping ‘renal impairment with failure”, the combo caused such problems in 18% of those patients, 12% i the evero group. Not good news for those of us with one kidney, so something to be monitorly VERY carefully.

The other ‘usual suspects’ in the side effects in the combo were hypertension 42% vs 10%, diarrhea 81% vs 19%. Not surprising was a fairly high rate of ‘hemorrhagic events”, ie, bleeding problems in both groups, 32% vs 26%. And more.

Again, not easy, better than no treatments,or using everolimus alone. All these meds demand good communication with the treating team and patients. Sadly missing in this trial and in every other one is any real guidance as to which patients might best respond to this combo. Neither is there a neat comparison to the second-line use of Nivo or Cabo. Practice, practice, and be aware of your own health issues as to side effect potential as you look at these trials and your own situation.

http://www.multivu.com/players/English/7690031-eisai-lenvima-fda-2/ for the company’s review and videos by Dr. Sumanta Pal at the City of Hope and a spokemans from Esai.

Recent headlines called a new medication, Nivolumab, both a miracle or breakthrough and more. Is it hype or hope?Why is it so hard to sort out the reality?

Let’s go through the facts from the New England Journal of Medicine and ignore the headlines. First, its being in the NEJM is important, as it has passed review by other researchers. (Sadly missing in too many ‘breakthroughs”).

The new med, Nivolumab was compared against Everolimus, a second-line treatment. Therefore Evero is thought to be of lesser effectiveness than the first line meds. Second-line meds are generally used when others meds quit helping or their side effects are too hard. Automatically NOT the miracle cure, but another option when first-line treatments fail.

Should Nivo have been compared to the first-line meds? Being better in the first-line would be bigger deal, but we need more approved meds. Second-line treatments usually are easier to ‘beat’, as the new med must be better or less toxic. Again, more likely to be approved!

PATIENT CHARACTERISTICS

The study had 821 patients 24 countries, half using Nivo and half Evero. Patients were similar, 90% having had a nephrectomy, removing the tumor and some or all the kidney. Then the cancer spread, making metastases, (mets, for short). These patients had 1-3 treatments, first-line drugs like Sutent, a targeted therapy, and a few had used cytokines or even chemotherapy. Having had an mTOR inhibitor like Everolimus was not acceptable. Most had lung mets (67%), followed by liver(12%) and then bone mets (18%). Most with 2 or more sites of mets.

To enter the trial, the patient had to have had disease progression after their last treatment, within six months of enrolling in the trial. No doubt, some patients had greater disease progression than others, but had relatively good performance status, not completely bed-ridden or unable to function.

The median time from initial diagnosis of kidney cancer at any stage to entering the trial was 31 months; half had been diagnosed less than 31 months ago, and half more than 31 months before the trial. That range of time from diagnosis to trial was 1 to 392 months. That means that for some patients, they went a long time either fighting the disease since diagnosis, having a later recurrence, being treated, yet having disease progression years after the intial diagnosis. At least one person was diagnosed 392 months earlier. This is a good reminder to patients who have been told, “I got it all”. This darn stuff can return, so having a plan B is important. Again, the previous treatment failed and these patients got directed into this trial.

GENERAL RESULTS

Median Overall Survival (OS) is a measured when one-half of the total number in the group dies. Median OS for Nivo was 25 months with some patients still surviving at time of report, beyond the 25 months. For Evero, OS was 19.6 months, some of who were also likely surviving, as well. The OS of 25 months was clearly better with the Nivo group by this analysis. Nevertheless, half of all the 821 patients total died while on this trial from progressive disease. Of 183 of the 410 Nivo patients, 183 has died by 25 months, and 215 of the 411 Evero patients had died at 19.6 months.

There is no report of ongoing response here, but many went on to other meds, as explained below.

Median Progression Free Survival (PFS), measurable growth of disease, was 4.6 months for Nivo, 4.4 months for Evero. The median shows that half of each group, roughly 200 each had return of disease in less than 5 months! Again, these trial patients were pretty sick or at risk. All had been treated earlier, and had to stop previous treatments due to recurrence of disease. However, this shows a pretty quick return of disease or new growth from the base CT scan for nearly 65-70% of all patients.

One subgroup did a bit better than the 4 1/2 months median PFS. At six months after the start of treatment, there was a special subgroup was noted, about 1/3 of those patients–145 pts (35%) with Nivo, and 129 (31%) with Evero. Obviously they did not die or have Progressive Disease until after six months. The Nivo group had eventually had a median PFS of 15.6months, and the Evero group, 11.7 months. Their success pushed the median OS higher, especially for the Nivo group.

Obviously, there were some patients with far more aggressive disease in both groups, some dying before six months, and others not progressing to more disease until after six months. In contrast, nearly 1/3 of all the patients had PFS of 12-15 months, and much longer OS. What is the common characteristic in the most successful two groups in both arms of treatment? Not answered by this trial report.

The duration of treatment was longer with Nivo, and likely easier to tolerate. Since Nivo was given by IV every two weeks, the doses were most consistently received. Even so, 51% of them had dose delays, but no per dose reductions. Those people were seen by the medical team every two weeks.

The Evero group took oral meds, and 66% had dose delays or interruptions with 26% with at least one dose reduction. This would indicate that these meds could be hard to take, or perhaps lacking the same interaction with their medical team. Of course the Evero patients may have underreported how much of the medication they actually took!

However, the reported types of side effects were generally similar, but the more severe grade 3 and 4s effects in the Evero group.There were 2 treatment related deaths in the Ever group, none in the Nivo group.

POST PROGRESSIVE DISEASE

Even after the disease did progress, about half of patients in both groups stayed with their meds–despite ‘failing’, the researchers hopes that would continue to benefit, perhaps slowing the disease. In a local clinic setting or with a less experienced docs, their meds might have been stopped or changed. Afterall, those meds were no longer “working” and mets are growing. This approach is significant to consider, especially after multiple treatments. (The decision to keep giving a medication or increasing its dosage where tolerable is causing some changes in treatment in a number of the targeted therapies.)

Perhaps because of being in a trial or getting care than was more expert than most, one-half of patients chose to keep on the trial meds. Others crossed over to the med in the other arm or returned to existing non-trial meds. In some countries, there were likely fewer choices than in the US. There are no real stats as to survival for those on those who stopped taking the meds. It is reported that indicate that 55% of the surviving Nivo group and surviving 63% of the Evero group went on to other agents. About one-quarter of the Nivo group shifted to the Evero. Of the Nivo group, 36% shifted to axitinib.

Sadly, as per the chart in the New England Journal of Medicine, all these patients had died by 30-33 months post enrollment. However, it is again not clear what was effect, if any on that period from the non-trial drugs. Of the 227 who stopped Nivo for any reason, nearly half shifted to Evero. Of those who stopped Evero, 140 went to Axitinib.

DURABLE RESPONSES? HOW LONG? FOR HOW MANY?

The writers of the study say that there was a higher number of objective responses with Nivo vs Everolimus, and that many (of the Nivo group) “were durable”. There is no definition of ‘durable’. My question is “What equals durable?”. We patients really want a cure, but are very grateful for anything that pushes the cancer back, slows it, stops in from growing any further. Nevertheless, we do want those responses to last. The clearest reference to durable responses is a note that 32 of the Nivo patients and 6 of the Evero patients had a response that lasted more than 12 months. But in an unexplained statement, the median duration of treatment was just 5.5 months for the Nivo patients, 3.7 for the Evero group. It seems that there was not an extension available, or that the patients moved on to a different treatment or passed away.

CONCLUSIONS AND EDITORIALIZING AGAIN

It seems that Nivo is more helpful for some patients than others in this group previously been treated with other TKIs. This is NOT A SILVER BULLET. There would be greater value to know more about the molecular nature of the tumors of the responding and the non-responding patients. We desperately need to know for whom any of these drugs is likely to be more effective. The headlines that don’t discuss that challenge underserve us, as does the design of the trial that does not elicit the more nuanced, genomic data that could be forthcoming!

We all know that headline claims are more wonderful than the reality. The story of RCC medication development is that of more and more help in a difficult disease, making mixed progress, while the other researchers find out that RCC is really many diseases. Clear cell is probably better defined as being made up of four types, Papillary Type 1 and Type 2 being further divided into three Type 2, then there is chromophobe, clear cell papillary and the really odd versions of RCC. I known this, and so do you. But why don’t the researchers incorporate those definitions and monitor the patients with those various subtypes as they go forward?

Once you reach a ‘certain’ age, you are horrified, but not surprised to get a cancer diagnosis, or hear about it in a loved one. That same cancer in a young person is even more horrifying, we instinctively know.

Most kidney cancers (and there are more types than we previously knew) are found in people in their 60s and 70s. Bad enough, but a cancer called by the same name and found in a younger person is often a very different cancer, with a very different prognosis.

Some new research recognizes that special attention should be paid to those RCCs found in patients 46 years of age and younger. Why is this?

The quick answer is that this may represent a more aggressive kidney cancer and/or be of a familial or hereditary nature. That important distinction has researchers strongly recommending that young patients be referred for genetic testing. This can explain those special risks and create more appropriate treatment plans, and alert other family members as to special monitoring. Critically it may change the approach to any removal of the kidney and/or tumor.

Typically a small renal mass might be monitored or removed by either surgery or some laser ablation. If removed, the tumor can be assessed by a pathologist–a look under the microscope.Without a prior biopsy, the ablated tumor will not be examined, and no genetic testing can be done.

BIG HOWEVER HERE: even with a good pathology report, that may tell only what that tumor looks like–not what pushed it to grow, i.e., the genetic drivers. And those genes don’t go away with the tumor, so the risk remains that more tumors will grow, maybe in the second kidney, or in the partially removed kidney. Plus the rest that can happen with cancer…

An 75 year old whose small renal mass is removed will likely function well with one kidney. That same tumor in a 35 year old creates another challenge. If that tumor is driven by familial genes–not just by sheer bad luck–more tumors on the other kidney may be in the works. A partial nephrectomy must be considered. The risk of more tumors emerging in that kidney AND the other kidney is high. The younger patient needs decades of good kidney functioning, but those decades carry the risk of the emergence of more mets.

What else should trigger a genetic testing?

Quick answer: anything that doesn’t look like the senior citizen with a single tumor in one kidney. More officially below:

Early onset of kidney cancer is 46 years or less.

Bilateral (two-sided) or Multifocal (many locations) kidney tumors

Family history of kidney cancer, 1 or more close relative, 2 or more in more distant relatives

Kidney cancer with either a mix of other tumor types roughly related to kidney cancer or with lung cysts or pneumothorax (air leaking out of lung into chest cavity)

Personal or family history of kidney cancer syndromes.

The above list is from Yale School of Medicine, Professor Brian Shuch, who work includes dealing with heredity forms of kidney cancer.

More small renal masses found at an earlier age in more patients, as our imaging techniques improve and more CTs scans are done. Not all will be hereditary, and many will be sporadic or out-of-the-blue kidney cancers. Those are likely due to the sheer chance. Things go wrong as trillions of cells divide and make DNA mistakes along the way. Years of environmental damage may overwhelm the body’s ability to correct those DNA mistakes–i.e., the immune system gets overwhelmed, tricked, tired, etc.

Kidney cancer found at an early age or with the bilateral/multifocal tumors simply must be tested as to it genetic origins. This gives information critical to protect the rest of the kidney(s) and to participate in treatment that is more helpful. Finding an effective treatment will still be a challenge, but proper treatment requires knowing exactly which kidney cancer you have. From there, a real plan can be developed.

Just as I remind all readers to work with an experienced RCC oncologist–not just a surgeon and/or urologist (sorry guys, we need a team)–those who fall into this early and hereditary renal cell carcinoma category must also work with super specialists.

The person to contact at NIH is genetic counselor Lindsay Middelton at (301) 402-7911. She is with the National Cancer Institute’s Urologic Oncology Branch. An introductory link is below to the NCI and two other rare kidney cancer organizations.

Being diagnosed with kidney cancer is a stunner. Facing surgery and endless, oft unanswered questions changes your life. Patients with small tumors, easily removed, are often told not to worry about it coming back. Of course, there is ALWAYS the possibility that even small “I got it all tumors” can recur. Sadly, the current guidelines fail to catch about 30% of recurrences, using the 2013, 2014 guidelines. These guidelines were from an earlier era, where there were fewer small tumors found, so there was data lacking on long-term follow-up.

We patients ask? “Why not just take the meds that the patients with metastatic disease do? Wouldn’t that prevent it from coming back? If it works to fight the mets, why wouldn’t it prevent new ones from getting a foothold? “

Why not use the meds that they use now against metastatic disease? Why wouldn’t that work? Have they tested that idea?

In February of 2015, a study was released which comparing patient response to 1) sunitinib (Sutent),2) sorafenib (Nexavar), or 3) placebo (no real medicine). This three-arm study included 1,943 patients who had locally advanced clear cell and non-clear cell histology RCCs. They were thought to be at high-risk for recurrence of their cancer, and might benefit from “adjuvant” therapy. The researchers hoped that they would see a 25% improvement in time to recurrence of disease with the meds vs no meds.. That would means that the typical 5.8 years median Disease Free Survival (DFS) would go to 7.7 years.

Sadly, there was no benefit to taking the active drugs compared to the placebo. More sad is that the patients had side effects associated with the drug, referred to as “adverse events”. In fact, many dropped out of the active agent arms into the placebo arm, certainly knowing that the med they were taking were anti-cancer meds. Those “adverse events”, severe fatigue, hypertension or hand-foot reactions, were observed in those taking the active agents and rarely in the placebo patients.

The median time on the drugs was 8 months. That means half the patients were on drugs more than 8 months and half were on the drugs less than 8 months. Even those patients starting with lower doses of the drugs fared worse than the placebo group.

Despite taking the medications and enduring the side effects, the recurrence was about the same. With medication or without, these patients, as groups, did the same. Those taking the meds had Disease Free Survival of 5.6 or 5.7 years, similar to those not taking any real meds. There was no real added benefit to these patients. Certainly the quality of the life was affected by the side effects, and the constant reminder of the spectre of more cancer.

What can patients learn from this study?

The fear of recurrence is real. After all, the expected time until the disease progressed (love using that term for cancer!), was about 5 1/2 years. These patients were carefully monitored with CTs on a regular basis, which caught their recurrences as soon as possible. Had they not been in this trial, it is reasonable to expect that many would not have received those scans and not know of the recurrence as it happened.

The reality is that the typical patient may or may not continue to be monitored. Even those who passed the 5 1/2 year mark without recurrence may not realize that RCC can come back. Again, 30% of recurrences in small, non-metastatic disease are not caught. One can assume that the higher risk group in this trial would also be at risk for that level of recurrence.

Take-home message: At present, nothing has been shown to prevent recurrence of this locally advanced disease. Even the non-metastatic small tumors that have sent out invisible “wanna-be mets”, and no one can yet guess who is at the most risk.

The best approach is to monitor yourself and your general health and to demand CT scans, especially in the lungs, where metastatic RCC is most likely to start. That does NOT mean an x-ray, as those mets would have to be about 1/4″ in order to be seen. My own lung mets were under that size when first found, but there were hundreds of them, and they grew quickly. Not visible on an x-ray, but growing every day.

Despite the disappointing study above, the ASSURE study, more clinical trials are recruiting patients for similar studies using drugs that have already been shown to be less active than those in the ASSURE study. I would be cautious in getting into such a trial, and would spend my energies seeing that my monitoring is extended at least until 10 years past my surgery–even with those “got it all” primary tumors.

Why don’t the various medications work better for RCC? Why do some patients do well, and others so poorly? Why is it so hard to choose the right medicine?

This lecture explains why patients and doctors must play the guessing game in treatment. It may be the most important lecture in this blog, and provides an explanation as to why RCC cancers behave so differently, even those variants with similar pathologies. (My notes are in italics, like this, added to help with this complex discussion…I hope.)

“I am going to talk to you today about the genetics of kidney cancer and how I believe it is paving the way for the next generation therapies. There are no significant disclosures.What is the problem? This is a problem that we are well aware of some nowadays. We’re using one drug for all patients with kidney cancer. You may imagine that these are all patients with metastatic renal cell carcinoma. But it is a heterogeneous population. Some have the red tumor, some of them the green tumor, and the drug may work with a subset of patients, but it may not work for another subset of patients.(Left half of the slide with the meds not reaching the patients with GREEN tumors.)

We should be evolving to a paradigm where patients with different tumors are treated with different drugs. (Right half of slide shows Drugs A and B going to different subsets of patients.)In the context of renal neoplasms , as you are well aware, we have kidney cancer with clear-cell carcinoma which accounts for the vast majority (75%) of that, and that’s going to be the focus of the first part of the talk.

The work from the Sanger Institute by Andy Futeral and Michael Stratton led to the identification of mutations in the PolyBromo1 gene. Polybromo1, like VHL, the most commonly mutated gene in clear cell renal cell carcinoma, is a two-hit tumor suppressor gene. That means both copies are mutated in tumors. They identified through truncating mutations in approximately 41% of clear-cell RCC. PolyBromo1 encodes BAF 180, which is a component of a nucleosome modeling complex which may regulate, among other processes, transcription.” (Peg & Wikipedia say that transcription is the first step of gene expression, where DNA is copied into RNA, giving instructions. Pretty basic cell info.)

“Work from my laboratory led to the discovery of another gene mutated in RCC, the BAP1 (BRACA1 associated protein-1) gene. Like the BPRM1 and VHL, BAP1 is a two-hit tumor suppressor gene, but it is mutated in only about 15% of sporadic clear-cell RCCs.

This work was done focusing on tumors that were of high grade. Indeed, we found there was a correlation between BAP1 loss and high grade, and also activation of the mTOR1 pathway. BAP1 encodes a nuclear deubiquitinase. Of greatest interest, mutations in BAP1 and BPMR1, we found, are largely mutually exclusive. This is shown this more detailed the next slide.

What you are seeing here are 176 tumors, each in a row. These are tumors that have a deletion in PBMR1, these are tumors with the insertion, this with a point mutation (referencing the various symbols P). All the tumors in blue are tumors that have a mutation. As you can see most of the tumors, we see with PBRM1 mutations do not have mutations in BAP1. (Column 4 has many BAP1 mutations.)

(in last column) Here you have some tumors with mutations in BAP1, and we only identified three tumors that had mutations in both genes. (Very end of column 4) The probability of having mutations in both genes was statistically significant. Based on the individual mutation probability, we would have expected 13 tumors to have both genes. Only three were found, suggesting that BAP1 and BPRM1 mutations are largely mutually exclusive.

We went on to performing a meta-analysis. This is looking at data from that Beijing Genome Institute, at Memorial Sloan-Kettering and this from the TCGA (The Cancer Genome Atlas). As you can see, even though the numbers are small, the numbers of tumors with mutations in both BAP1 and PBRM1 was reduced, compared to the expected number of tumors based on the individual mutation frequency, and the p value was statistically significant.I’m going to go through these and not spend much time, but suffice it to say that that we found that these tumors that have had mutations in BAP1 have a characteristic gene expression signature, and the tumors that have mutations in PBRM1 also have a characteristic gene expression signature. These gene expression signatures do not overlap. These are tumors that have different gene expression patterns and different biology. (Per Peg: this shows that these are biologically different tumors. Notice the different patterns of red and blue below.)

We think this establishes a foundation for the first molecular genetic classification clear-cell RCC. In our series, 55% have mutations in PBRM1, and 15% of the tumors have BAP1, and including 3% have mutations in both. (The balance are wt, wild-type, meaning as it occurred in nature, not mutated.) We also observed that there is a statistically significant correlation between mutations in BAP1 and high grade (tumors), and mutations in PBRM1 in low-grade (tumors).

So that let us to propose the following model. This is a model based on the fact that, very interestingly, VHL, BAP1, and PBRM1 are all located on chromosome 3. In fact, the short-arm of chromosome 3, and this is an area that is deleted in the majority of patients with von Hippel-Lindau-associated renal cell carcinoma, as well as in the majority of sporadic renal cell carcinoma, depicted here in blue. (VHL associated RCC is an inherited type of RCC, not arising from a mutation…but along the same chromosome.)

You can imagine that with a single deletion, the kidney cell is losing, in fact, four copies or one copy of these four different tumor suppressor genes, the BAP1, PBRM1 and VHL.

We have proposed the following model. We believe that renal cell carcinoma, and this is consistent with data from Gerlinger and colleagues, that it begins with an intergenic mutation in the VHL gene. And this is followed by loss of 3p, with a concomitant loss of one copy of all of these tumor suppressor genes. We then think that a mutation in PBRM1 leads to the loss of PBRM1 function, which is a two-hit tumor suppressor gene and low-grade tumors, whereas the mutation in BAP1 is associated with the development of high grade tumors.

REFER to ABOVE PIE CHART re High and Low Grades

This model also predicts that patients with BAP1 and PBRM1 deficient tumors may have different outcomes. So we simply took those patients whose tumors we had analyzed and asked what happens to their outcomes. (The UTSW and TCGA cohorts reference tumors from different institutions. Blue lines are the PBRM1 deficient tumors, and red lines the BAP1 tumors. The lines which fall the quickest show poorer overall survival.)As you can see here (LEFT), we found that patients with PBRM1 deficient tumors had a significant better Overall Survival than those who had BAP1 in their tumors, which had a Hazard Ratio for that of 2.7.

We did a similar analysis with the TCGA cohort, and we found (RIGHT) essentially the same result in the same hazard ratio of 2.8, indicating that BAP1 mutant tumors are associated with worse outcomes in patients. This data has now been reproduced by Hakimi and James Ying at Memorial Sloan Kettering, as well as the TCGA with their own analysis and our colleagues in Japan and Tim Eisen.

There are some limitations of sequencing. We all like next generation sequencing, but it has some limitations. First, it focuses on DNA. Secondly, it uses pooled material. Thirdly, it has reduced sensitivity which is a consequence of contamination by normal cells. In addition, a negative result does not guarantee that there is normal function. There is poor discrimination of subclonal mutations in different cell populations. So as a consequence of using poor material, we cannot tell whether these mutations are found in the same cells or different cells. Typically, it involves fresh frozen samples which are reduced in numbers, and consequently has limited power for doing some analysis.

Interestingly enough, immunohistochemistry (IHC), which we’ve use for a long time is a lot more precise. This is because actually you get information at the cellular level, and you get information about the protein. I mentioned to you that BAP1 is a two-hit tumor suppressor gene, which basically means when it gets mutated, you lose both copies.As you can see here–this is the same series showed before. These are here in blue the tumors that had mutations, in the second column, you can see blue and brown, the results by immunohistochemistry. That is done by IHC. And BAP1 is a nuclear protein, as you can see in these beautiful nuclear staining.

The bottom line is the majority of tumors that had mutations (referencing blue column data points) had lost BAP1. There were two tumors with point mutations where we were able to detect the protein. But there were three additional tumors we could not detect protein, but where there was no protein. If there is no protein, there cannot be functioning.

The rest of the tumors, with one exception, were all positive. So compared to mutation analysis, in fact, there is positive predictive value is better and the negative predictive value is pretty similar.

We have used this immunohistochemisty test in conjunction with the Mayo Clinic, looking at their registry with over 1300 with localized ccRCC. As you can see, looking here with people with specific RCC survival, patients with RCC tumors that have BAP1 positive tumors have significantly better survival outcomes than those who have BAP1 negative tumors, again with a Hazard Ratio of approximately 3.

Importantly, this test allows us to identify tumors that are simultaneously mutated for BAP1 and PBRM1. This is important.Slide A Slide B

(This slide in presented in two parts to help understand lecture.)
Upper half of slide showing stained pathology images.)

I am going to show you look at this tumor over here (upper left path image A) you can see that the tumor cells, there are some that have brown nuclei, but these are the endothelial and the stromal cells (along the edge of the white). The tumor cells are negative for BAP1.

This is the immunohistochemistry (upper right path image B) for PBRM1, where we find the same thing,where the tumor cells are negative for PBRM1.

Now (left path image C) compare these tumors with these images below. You can see here that the tumor cells positive for BAP1 in this area (the upper right corner of the path image C) and they are negative (in the lower left corner of Slide C), where you can see specific nuclei which look blue over there.

Now if you look at the parallel section (Lower right path slide D) you can see the area that was BAP1 positive (left hand side???D) is actually also PBRM1 negative, and the area which was BAP1 negative is actually PBRM1 positive.

So what you have over here (inthe upper slides A & B) is a tumor which has lost BAP1 and PBRM1 in the same tumor region, the same cells. The tumor has lost BAP1 and PBRM1 in independent regions. Obviously these tumors will be acting differently and the tumor we are most interested in is this tumor type (in the upper left image A).

You have seen in our immunohistochemistry test. We believe we can separate clear cell renal cell carcinoma into four different molecular subtypes. This is looking at Mayo registries, where the patients with best outcomes are those whose tumors are well-typed for PBRM1 and BAP1. Then you have 2) patients that have tumors which are deficient for PBRM1, 3) patients that have tumors that are deficient for BAP1, and 4) patients whose tumors are deficient for both. As you can see the Hazard Ratio is 1.3, 3.2 and 5.2, respectively.

As I mentioned to you at the outset, that these tumors were underrepresented and indeed in this very large cohort, we found a very large significant underrepresentation with 1.8% of the tumors being double mutant, compared to 5.3% (which would been expected) with a very highly significant p value, again indicating there is mutual exclusivity–for reasons we do not yet understand.

Importantly BAP1 and PBMR 1do not predict outcomes independently of SSIGN. SSIGN is the nomogram created by the Mayo Clinic, which is based on Stage, SIze, Grade, and Necrosis. This is the SSIGN nomogram; this is the independent validation. You can see the curves separate beautifully, depending upon the score.

Now another question I submit to you. Should nomograms trump biology? In other words, if they live the same, “What do I care?” That has been the traditionally the thinking in the clinic. But look at these animals. A bullfrog and a grizzly bear also live about 30 years. However, they’re very different. The same is true for cottonmouth, a beaver or hummingbird or a newt. So even though they live the same, they are actually quite different!

We should be probing deeper and in fact, they should be dealt with differently!

I believe that clear-cell renal cell carcinomas are in fact divided for at least four different subtypes. There are tumors that are wild type for both BAP1 and PBRM1, tumors that are PBRM1 deficient, tumors that are BAP1 deficient, and tumors that are deficient for both. In the future we are going to see different treatments for different tumor types.

In conclusion, the discovery of BAP1 and PBRM1 mutations in clear cell renal cell carcinoma, how they relate to each other, and how they affect outcomes establishes the foundation for the first molecular and functional classification of sporadic ccRCC.

These two genes define for distinct subtypes, which I just went over and you have the Hazard Ratios and p-values written down there. These two tumors are not only associated with different outcomes, but they are also associated with different activations on the mTOR1 pathway and gene expression. Finally we identify mutations in BAP1 which define a novel clear-cell renal cell carcinoma syndrome. I have forty seconds left!

I will go through these very quickly. Suffice it to say, we have also done molecular genetic analysis in non-clear-cell renal cell carcinoma, papillary, chromophobe, oncocytomas, This is now in press in Nature Genetics.

We found that papillary clear-cell carcinoma have more mutations than clear cell carcinoma, whereas chromophobe and oncocytomas have significantly lower mutation burdens, which is depicted there.

These are some genes we found overrepresented– five seconds! You can see the copy number alterations, gene expressions. Anyway, these papers will be coming out next week.

Finally, to acknowledge people who did the work in my laboratory, Pena-Llopis. We have had a close collaboration with the people at Mayo Clinic, and also the group at Genentech. We also work very closely with our surgeon and Payal Kapur, our pathologist.

Most people are not surprised that there is no ONE thing called cancer. Tumors in all the organs or invasive cells in the blood or bones are referred to as cancer, but start when cells go wrong, whatever the cause. As soon as you are told you cancer, whatever it, the quest begins to find out exactly which cancer it is. With kidney cancer, or its more melodious name, renal cell carcinoma, there seem to be endless variations on what may be called kidney or renal cancer. To treat it requires a very careful analysis of what is really is, starting with the pathology of the tumor when it is biopsied. With kidney cancer that biopsy is usually done after surgery for the tumor. That biopsy will describe the shapes and type of cell in the tumor, which can be mix of types. And then the real work begins.

A recent article in “European Urology” reviewed the mix of HEREDITARY renal cancers, those that arise due to one’s background. More common are the “sporadic” kidney cancer that could arise out of the blue or in response to some environmental toxin. There are ten Heredity Renal Cancers, or HRCs. My goal is to alert the reader to the possibility that his cancer might be one of these. This would affect treatment, and may suggest the need to test family members.

If you have kidney cancer or RCC, you may be familiar with “clear cell” or “papillary” to refine the description of the cells in the tumors. This may not be the whole story, as those HRCs—the hereditary kinds—may manifest a mix of ways, including as clear cell or papillary histology.

The most common HRC is Von Hippel-Lindau (VHL) disease, with both benign or malignant tumors. RCC can be found in a 24-34% of VHL patients, appearing at mean age 39 years (far younger than non-heredity RCC), and often with multiple tumors and in both kidneys. Cysts which appear not to be malignant must be watched–they have the potential to become malignant over time. Generally they are managed based on the size of the largest of these lesions. Clear cell RCC is the one VHL-related subtype.

Hereditary papillary renal carcinoma (HPRC) is rarer, and typically occurs later in life. Papillary tumors are the only phenotype with HPRC, and patients often develop numerous tiny tumors, 1000 or more. These tumors are considered type 1 papillary renal cell carcinoma (pRCC) with a low nuclear grade, monitored with CT scans, and some do metastasize, though this is rare. The MET gene is implicated in the growth of these tumors.

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is newly identified as a HRC. Rarely do patients develop RCC, but are susceptible to developing multiple leiomylomas, which are generally benign. When there is early onset of HLRCC, then RCC is found in about 20% of those patients. These tumors can be aggressive, and about 2/3 display a papillary pattern. Such tumors tend to be hyper-vascular.

Birt-Hogg-Dube (BHD) syndrome is quite rare, about 1 in 200,000 people, and thereby likely under diagnosed. This raises the risk of developing kidney tumors, which occurs in 25-35% of BHD patients, and at mean age of 50. These tumors have varying histologic subtypes, generally chromophobe RCC or hybrid variants. And there can be variants in the same tumor or within the kidney. There is a risk of metastases, though rare. The characteristic skin lesions of BHD syndrome are not malignant.

Even more rare is Tuberous Sclerosis Complex (TSC), which can manifest itself in renal lesions, cysts and occasionally, RCC, the latter at a young, average age 28. Neurologic complications can accompany this syndrome.

SDHB-associated paraganglioma/phaeochromoytoma is another heredity condition which may give rise to a mix of renal tumor, including clear cell RCC, chromophobe RCC and oncocytomas, i.e., a mix of histologically different types.

An HRCmay be suspected in patients with a family or individual history of renal tumors, in the instance of both kidney having tumors, or one kidney having multiple tumors or in early-onset renal tumor, i.e., under 50 years of age.

Clinical diagnosis can be further refined by genetic testing, and thorough review by an experienced uropathologist is fundamental to the diagnosis. First consideration would be a VHL analysis and genetic analysis of SDHB and FLCN genes, as warranted. Patients with type 1 papillaryRCC should be considered for MET analysis. The presence of clinical symptoms related to any of the syndromes will guide the gene screening. Testing on family members may well be warranted.

With these cancers, it is possible to have multiple lesions and affect both kidneys. Thus, treatment should preserve renal function and control the risk for metastases. Use of ablation to retain maximum renal function may be preferable to partial nephrectomies, for example.

Though these heredity renal cancers arise in a different manner than the more common sporadic RCC, the study of the molecular pathways provide some insight into new therapies for those patients as well. Thanks always to those researchers who help in this struggle for information, as that is essential to provide treatments.

I love this study, as it really symbolizes the tremendous change that has occurred in kidney cancer treatment these last 6 years. It is remarkable that the 124 patients are described as having already received first- line treatment, and were now in their second-line. These same metastatic patients might have received neither just six years ago.

The study was really not to compare the response to the treatments received, whether Sutent (sunitinib), Nexavar (sorafanib), or placebo. (Why any party chose or was chosen to receive a placebo is another, darker question.) That the median follow-up was 80 months is a triumph by itself. This is in contrast to the clinical trials that often show just a few months extra time which we and politicians can focus on, when the reality of much longer responses is clearly shown here. Of course, these longer survival times came from those trials which showed those few months–and this shows the reality of many more months and years of life!

Metastatic tumor burden(TB) was measured, based on the size of the sum of the longest unidimensional diameter of each targeted lesion. The additional increase of 1 cm (about 3/8”) was significant in predicting response to the medications. Siimply, adding the one-direction measure of the lesions and comparing them showed that more tumor was a bigger problem.

One can also assume that to remove as much tumor as possible may be helpful in maximizing the benefit of the meds given, although this study does not address the actual types and locations of the mets, nor indicate why no other therapies, surgery or ablation, were used. With 124 patients this would represent a mix of individual experiences, more like the typical patient group.

What does “median follow up of 80 months” really mean? A median is not an average, but a measure of the time point at which ½ of the population studied had follow up less than 80 months and ½ had follow up for more than 80 months. Since this is considered a long time in clinical trials and becomes more of a longitudinal study, we may never know the average length of time that these patients had either PFS (Progression Free Survival—time until the mets began to grow again) or OS (Overall Survival). In any case, we are aware that following this second-line of treatment, there are still more therapies and interventions which may be available. And even more options are up for FDA approval as I write.

All these options and the greater success of each muddies the study waters, but clarifies the hopes of those with metastatic RCC, or are at risk. This study proves that tumor burden (TB) is a disadvantage. Most patients have naturally assume that more cancer is worse for you than less cancer—who knew? But this gives weight to the notion that the removal of some tumors, if not all, can be beneficial used with targeted therapies. In the past, some oncologists have discouraged additional surgery in the light of metastases, with the implicit message, “It’s too late, and won’t help you anyway.” Not the doctor for me.

The story is quite different right now, but patients may need to tell this to their doctors–in the language that the doctor speaks. Certainly, there was a time at which doing more surgery for mRCC patients added little, if anything, to survival and probably even less to the quality of life. That no longer is the case, and those older studies no longer have meaning. While each patient must be treated as an individual, in light of all the variables that impact his health, there is increased optimism for the metastatic patient. Aggressive and early treatment can no doubt extend life and make it worth living.

Dr. Suzanne Topalian, professor of surgery and oncology at Johns Hopkins Sydney Kimmel Cancer Center presented a paper at a recent ASCO meeting which caused quite a stir in the kidney cancer community. Her short talk is in the link below, with the transcription to follow.

What’s the good news about being anti? The complex interplay of our immune system and the manner by which cancer escapes its notice is a challenge to the researchers, but this trial shows that there are many ways to interrupt the growth of cancer cells. This trial and another mentioned offer new hope to patients who have already exhausted earlier options.

Not only did this trial show that this drug could provide relief to some patients with kidney cancer, lung cancer and melanoma, the presence of this anti-body may serve as a biomarker, and may predict which patients might respond to the drug treatment. Another step forward and more hope for all of us.

Today I would like to describe do the clinical activity the safety and potential biomarker of clinical response to the drug PD-1, which is an anti-body therapy. PD-1 or Programmed Death-1 is a molecule that is expressed on the surface of activated immune cells it plays a very important role in suppressing the tumor by suppressing antitumor immunity.

In order to understand how anti-PD one works you need to understand a little bit how the immune system works, and how it can fight cancer. T-cells are a central cell type in the immune system that fight cancer. T cell function is regulated by two different signals. Signal one is a specificity signal, whereby the T cell recognizes its target and here we are talking about the targets being components of tumor Cell., but then you need a second signal to tell, the T Cells what to do, a regulatory signals. That signal can be either positive or negative.

If the signal is positive or stimulatory, t he T-cells become activated. They secrete cytokines. They can kill tumor cells. They proliferate; they percolate throughout the body, seeking out and destroying tumor cells. All of that is what we want to see.

But after activation, T-cells naturally begin to express the molecule PD-1 on their surface. This is will turn the T-cells off. If they encounter the partner molecule PD-L1 or PD ligand 1, tumors cells can express PD-L1. So the interaction between these two molecules becomes a protective shield, that shields the molecule from immune attack. Even if the T-cell can recognize the tumor and they can get to the tumor, once they get there and they are expressing PD-1, if the tumor is expressing PD-L 1, the T-cells will be turned off. The anti-PD-1 antibody is a blocking antibody to PD-1. It interrupts this interaction and functions to rescue exhausted T-cells and to enhance anti- tumor immunity.

The phase 1 trial of anti-PD-1 that I’m describing today is a multi-dose regimen in which something is given the outpatient in the outpatient clinic once every two weeks. Patients were treated for a cycle of four treatments over eight weeks. At the end of which, they were restaged. Patients were eligible for these trials if they had advanced metastatic melanoma, kidney cancer, lung cancer, prostate cancer, colorectal cancer with progressive disease after having had at least one prior systemic therapy.

But they were allowed to have up to five of the therapies. Generally these patients who came on this trial had good performance tab status. But they were heavily pre-treated. Approximately half of them had at least three prior therapies be before they came onto the trial.

After the first cycle of treatment if patients had rapid continuation of disease or clinical deterioration, they went off study. If they had unacceptable side effects, the patient remained on study. They did not receive any more drug, but they continued under observation. If the patient demonstrated tumor regression or stable disease or even if they had some progressive disease, but were clinically stable, we continued to treat those patients until we saw confirmed Complete response, worsening or progressive disease or unacceptable toxicity. We could treat patients on this trial continuously for two years. After, they went into a follow up phase.

Here I’m showing you the drug-related adverse events are side effects that occurred in at least 5% of 296 patients which was the total patient population on this trial You can see that serious side effects were encountered in 14% of the patients. The most common side effects are listed here (fatigue, rash diarrhea, pruritis, etc.) There other side effects that are not listed here because they occurred less frequently. Many of the side effects were consisted with the side effects with over immune related causality as you might expected if you release the brakes on immune responses. As we are seeing anti tumor responses, you might also see immune-related sided effects.

We did see three treatment related deaths on this study. This was in 1% of the patient population due to pneumonitis, or lung inflammation which we’ve believe has an immune-related etiology. Over the course of time we developed better ways to identify people who are at risk for the side effect and also better ways to detect it early on and to treat it aggressively.

Also note that only 5% of all patients treated on this trial had to discontinue treatment, due to related side effects so in general the treatment was well tolerated in an outpatient setting, and in general the side effects were manageable.

This is showing the clinical activity of anti-PD-1 antibody in three different types of cancer across a wide range of doses. (Showing doses (mg/kg) of 0.1-10 for melanoma, 1-10 for lung cancer, and 1 or 10 in RCC). The largest number of patients in this treatment population of 236 patients who had at least six months of follow-up were 94 with melanoma. We had 26 patients (28%) who had objective responses. An objective response means either a complete response or a significant partial regression of cancer.

We also saw stable disease that lasted at least six months in another 6% of patients. Among lung cancer patients we saw patients with squamous as well as non-squamous subtypes we saw a CR plus PR of 18%, and with a patient population of 76 and again 6% with stable disease, with another group of patients with stable disease (referencing 7% of lung cancer patients.)

Finally in kidney cancer (33 patients), 27% had a response rate and 27% who had prolonged stable disease. There were 31 patients on this trial who had a response that occurred at least one year ago and among those 31 patients, two thirds of them had a response that persisted for more than one year. One of the remarkable features about this therapy is that it can induce very durable responses in otherwise treatment-refractory patients with advanced disease. We did not reserve any objective responses in 19 colon cancer patients or 13 prostate cancer patients.

Finally I’d like to draw your attention to a possible molecular marker that would allow us to predict which patients are most likely to respond to therapy.

In a subset of 42 patients on this trial, we examined pre-treatment tumor biopsies for presence of PD-L1—and again this is the partner molecule to the PD-1 that is expressed on tumor cells. What we found was a correlation between the expression of PDL-1 on tumor cells and here I am showing you the pre-treatment staining biopsies.

I am showing you with its ringed expression an example of melanoma, kidney and cancer in a sample of lung cancer. When we saw this kind of expression in that group of patients we had a 36% objective response rate. If we did not see that expression on the surface of tumor cells we did not had no responders. I would stress that these are very preliminary data but give us an important lead for further investigations and potential biomarker development.

In conclusion anti-PD-1 antibody–BMS 936558– can be administered safely in an outpatient setting for heavily pretreated patients with durable clinical benefit for patients with lung cancer, melanoma and kidney cancer.

These results will be released tomorrow, as you know in the New England Journal of Medicine, which is under embargo until early tomorrow morning. At the same time in the New England Journal, there’s a companion paper with the blocking antibody against PDL-1. The lead author of that paper here is Dr. Julie Braemar of Johns Hopkins and shall be available to answer questions at the end of session.

We found responses also in melanoma and lung cancer and kidney cancer with a blocking antibody against PD-L1, so we feel these two studies are in a sense bookends to point up the point the importance of the PD-1 pathway in cancer therapy across multiple histologies.

The preliminary data correlating PDL-1 expression in pretreatment tumor biopsies with outcomes needs to be further explored and that’s an area of active investigation. Finally controlled clinical registration trials of this drug with patients with the three types of cancer that seem to respond are planned. Thank you for your attention.